Ergoline analogues

ABSTRACT

This invention relates to pharmaceutically acceptable ergoline analogues and salts thereof. In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament.

FIELD OF THE INVENTION

This invention relates to pharmaceutically acceptable ergoline analogues and salts thereof. In particular, though not exclusively, the invention relates to formulations and uses of the same as a medicament.

BACKGROUND TO THE INVENTION

Ergoline is the main structure for a class of alkaloids including the well-known lysergic acid diethylamide (LSD). The chemical formula of LSD is:

Various synthetic modifications to the structure of LSD have been made in the prior art. However, such modifications often result in a decrease in activity. Ineffective docking/binding of these compounds to the appropriate receptors may result from such structural modifications.

There remains a need in the art for ergoline analogues, and improved compositions and uses thereof.

SUMMARY

Herein disclosed is a compound of Formula (I) wherein:

-   -   X is selected from H or C₁₋₆ alkyl (optionally, X is methyl or         isopropyl); and     -   Y is selected from a bond, O, CONH, NH, N(C₁₋₆ alkyl),         A-(CH₂)_(n)—B, wherein         -   A is O, NH or N(C₁₋₆ alkyl), wherein         -   B is a bond, O, or NH, wherein         -   n is 1 to 4; and     -   Z is selected from H, OH, NH₂, NHC₁₋₆ alkyl, N(C₁₋₆ alkyl)₂,         C₁₋₆ alkyl, C₆₋₁₀ aryl, SO₂—C₁₋₆ alkyl, SO₂—C₆₋₁₀ aryl, C₃-C₁₀         heteroaromatic or heterocyclic group comprising one, two or         three heteroatoms independently selected from O and N; and     -   wherein X and Z are different;         or is a pharmaceutically acceptable salt thereof.

In a first aspect of the invention, there is provided compound of Formula (I) wherein:

-   -   X is selected from methyl or isopropyl; and     -   Y is selected from a bond, O, CONH, NH, N(C₁₋₆ alkyl),         A-(CH₂)_(n)—B, wherein         -   A is O, NH or N(C₁₋₆ alkyl), wherein         -   B is a bond, O, or NH, wherein         -   n is 1 to 4; and     -   Z is selected from H, OH, NH₂, NHC₁₋₆ alkyl, N(C₁₋₆ alkyl)₂,         C₁₋₆ alkyl, C₆₋₁₀ aryl, SO₂—C₁₋₆ alkyl, SO₂—C₆₋₁₀ aryl, C₃-C₁₀         heteroaromatic or heterocyclic group comprising one, two or         three heteroatoms independently selected from O and N; and     -   wherein X and Z are different;     -   or a pharmaceutically acceptable salt thereof.

In an embodiment the alkyl group is straight, branched or a cyclic alkyl group.

In an embodiment the alkyl group is a straight chain alkyl group. In an embodiment the alkyl group contains 1, 2 or 3 halogens.

In an embodiment X is methyl.

In an embodiment X is isopropyl.

In an embodiment Y is selected from a bond, O, CONH, NH or NCH₃.

In an embodiment Y is A-(CH₂)_(n)—B, wherein

-   -   A is O or NH, wherein     -   B is a bond, 0 or NH, wherein     -   n is 1 to 4.

In an embodiment n is 2 or 3.

In an embodiment Z is selected from pyridine, morpholine, SO₂—CH₃, SO₂-phenyl, 8-oxa-3-azabicyclo[3.2.1]octane and 2-oxa-5-azabicyclo[2.2.1]heptane.

In an embodiment Y—Z together form the group:

-   -   O—(CH₂)₃—N(CH₃)₂     -   NH—(CH₂)₂—OH     -   NH—(CH₂)₃—OH     -   NH—(CH₂)—OCH₃     -   NH—(CH₂)₃—SO₂CH₃     -   NH—(CH₂)₂—NH—SO₂CH₃, or     -   O—(CH₂)₂—NH—SO₂CH₃.

In an embodiment Y—Z together form the group:

-   -   NH-phenyl, pyridine, O-morpholine, NH-morpholine, NH—SO₂-Phenyl,         NCH₃—SO₂-Phenyl, CONH-Phenyl, 8-oxa-3-azabicyclo[3.2.1]octane or         2-oxa-5-azabicyclo[2.2.1]heptane.

In an embodiment there is provided one or more compounds selected from:

Number IUPAC SMILES Structure 001 (1S,2R)-2-(1H- indol-3- yl)cyclopropan-1- aminium [H]N1C([H])═C(C2═C1C ([H])═C([H])C([H])═C2 [H])[C@@]1([H])C([H]) ([H])[C@]1([H])[N+]([H]) ([H])[H]

002 (4R,6R,7R)-4-[N′- (3-hydroxypropyl)- N-methylhydrazine- carbonyl]-6- methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- [H]OC([H])([H])C([H])) [H])C([H])([H])N([H])N (C(═O)[C@]1([H])C([H])═ C2C3═C4C(N([H])C ([H])═C4C([H])([H])[C@@] 2([H])[N@+]([H])(C([H]) ([H])[H])C1([H])[H])═C ([H])C([H])═C3[H])C([H]) ([H])[H]

pentaen-6-ium 003 (4R,6R,7R)-6- methyl-4- [methyl(pyridin- 4-yl)carbamoyl]- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(C3═C([H])C([H])═ NC([H])═C3[H])C([H]) ([H])[H])C([H])([H])[N @@+]([H])(C([H])([H]) [H])[C@]1([H])C2([H])[H]

004 (4R,6R,7R)-6- methyl-4-[N- methyl-N′-(oxan-4- yl)hydrazine- carbonyl]-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C1 ([H])C([H])([H])C([H])) [H])OC([H])([H])C1([H])[H]

005 (4R,6R,7R)-4-[N′- (benzenesulfonyl)- N,N′- dimethylhydrazine- carbonyl]-6- methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N(C([H])([H]) [H])S(═O)(═O)C3═C([H]) C([H])═C([H])C([H])═C3 [H])C([H])([H])[H])C([H]) ([H])[N@@+]([H])(C) [H])([H])[H])[C@]1([H]) C2([H])[H]

006 (4R,6R,7R)-4-[N′-(3- methoxypropyl)-N- methylhydrazine- carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C) [H])([H])C([H])([H])C([H]) ([H])OC([H])([H])[H]

007 (4R,6R,7R)-6- methyl-4- {methyl[(1R,5S)- 8-oxa-3-aza- bicyclo[3.2.1]octan- 3-yl]carbamoyl}- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H]) [C@@]4([H])O[C@]([H]) (C([H])([H])C4([H])[H]) C3([H])[H])C([H])([H]) [H])C([H])([H])[N@@+] ([H])(C([H])([H])[H])[C @]1([H])C2([H])[H]

008 (4R,6R,7R)-6- methyl-4- [methyl(oxan-4- yloxy)carbamoyl]- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(OC3([H])C([H]) ([H])C([H])([H])OC([H]) ([H])C3([H])[H])C([H])) [H])[H])C([H])([H])[N@ @+]([H])(C([H])([H])[H]) [C@]1([H])C2([H])[H]

009 (4R,6R,7R)-4-[N′- (benzenesulfonyl)-N- methylhydrazine- carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [HJ)[H])═C([H])C([H])═C 3[H])C([H])([H])[H])S(═O) (═O)C1═C([H])C([H])═ C([H])C([H])═C1[H]

010 (4R,6R,7R)-4-[N′-(3- methanesulfonylpropyl)- N-methylhydrazine- carbonyl]-6-methyl- 6,11-diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3 [H])C([H])([H])[H])C) [H])([H])C([H])([H])C([H]) ([H])S(═O)(═O)C([H]) ([H])[H]

011 (4R,6R,7R)-6- methyl-4- {[methyl(phenyl- carbamoyl)amino] carbonyl}-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(C(═O)N(C(═O)[C @]1([H])C([H])═C2C3═ C4C(N([H])C([H])═C4C ([H])([H])[C@@]2([H]) [N@+]([HJ)(C([H])([H]) [H])C1([H])[H])═C([H])C ([H])═C3[H])C([H])([H]) [H])C1═C([H])C([H])═C ([H])C([H])═C1[H]

012 (4R,6R,7R)-4-[N′-(2- methanesulfonamido- ethyl)-N-(propan-2- yl)hydrazinecarbonyl]- 6-methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C3 [H])C([H])(C([H])([H]) [H])C([H])([H])[H])C([H]) ([H])C([H])([H])N([H])S (═O)(═O)C([H])([H])[H]

013 (4R,6R,7R)-4-[N′- (2-hydroxyethyl)- N-(propan-2- yl)hydrazinecarbonyl]- 6-methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]OC([H])([H])C([H])) [H])N([H])N(C(═O)[C@] 1([H])C([H])═C2C3═C4 C(N([H])C([H])═C4C([H]) ([H])[C@@]2([H])[N@+] ([H])(C([H])([H])[H])C1 ([H])[H])═C([H])C([H])═ C3[H])C([H])(C([H])) [H])[H])C([H])([H])[H]

014 (4R,6R,7R)-6-methyl- 4-{[(1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5- yl](propan-2- yl)carbamoyl}-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H]) [C@@]4([H])OC([H][H]) [C@]3([H])C4([H])[H]) C([H])(C([H])([H])[H])C ([H])([H])[H])C([H])([H]) [N@@+]([H])(C([H])) [H])[H])[C@]1([H])C2) [H])[H]

015 (4R,6R,7R)-6-methyl- 4-{[(1S,4S)-2-oxa-5- azabicyclo[2.2.2] octan-5- yl](propan-2- yl)carbamoyl}-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(N3C([H])([H]) [C@@]4([H])OC([H])([H]) [C@]3([H])C([H])([H]) C4([H])[H])C([H])(C([H]) ([H])[H])C([H])([H])[H]) C([H])([H])[N@@+]([H]) (C([H])([H])[H])[C@]1 ([H])C2([H])[H]

016 (4R,6R,7R)-4-[(2- methanesulfonamido- ethoxy)(propan-2- yl)carbamoyl]-6- methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(C([H])([H])C([H]) ([H])ON(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N) [H])C([H])═C4C([H])([H]) [C@@]2([H])[N@+]) [H])(C([H])([H])[H])C1) [H])[H])═C([H])C([H])═C 3[H])C([H])(C([H])([H]) [H])C([H])([H])[H])S(═O) (═O)C([H])([H])[H]

017 (4R,6R,7R)-4-{[3- (dimethylazanium yl)propoxy](propan- 2-yl)carbamoyl}-6- methyl-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(OC([H])([H])C) [H])([H])C([H])([H])[N+] ([H])(C([H])([H])[H])C) [H])([H])[H])C([H])(C([H]) ([H])[H])C([H])([H])[H]) C([H])([H])[N@@+] [H])(C([H])([H])[H])[C@] 1([H])C2([H])[H]

018 (4R,6R,7R)-6- methyl-4- [pentyl(propan-2- yl)carbamoyl]-6,11- diazatetra- cyclo[7.6.1.0², ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N1C([H])═C2C3═C(C ([H])═C([H])C([H])═C13) C1═C([H])[C@@]([H]) (C(═O)N(C([H])([H])C([H]) ([H])C([H])([H])C([H]) ([H])C([H])([H])[H])C) [H])(C([H])([H])[H])C([H]) ([H])[H])C([H])([H])[N @@+]([H])(C([H])([H]) [H])[C@]1([H])C2([H]) [H]

019 (4R,6R,7R)-6-methyl- 4-[(propan-2- yl)carbamoyl]-6,11- diazatetra- cyclo[7.6.1.0²,⁷ ⁷.0¹²,¹⁶]hexadeca- 1(16),2,9,12,14- pentaen-6-ium [H]N(C(═O)[C@]1([H]) C([H])═C2C3═C4C(N([H]) C([H])═C4C([H])([H]) [C@@]2([H])[N@+]([H]) (C([H])([H])[H])C1([H]) [H])═C([H])C([H])═C3[H]) C([H])(C([H])([H])[H]) C([H])([H])[H]

In an embodiment there is provided one or more compounds selected from:

Number Structure 020

021

022

023

024

025

As calculated and described further herein below, compounds 001 to 019 have good ‘Docking Scores’ (Kcal/mol) to target the modelled receptors and are synthetically accessible. As such, compounds 001 to 019 are demonstrated to be synthetically accessible and useful as medicaments for appropriate conditions involving the target receptors, or related receptors with the associated corresponding conditions.

Synthetic Docking scores Number Accessibility (Kcal/mol) 001 2.35 −8.579 002 4.39 −13.446 003 4.19 −12.761 004 4.55 −12.399 005 4.72 −12.957 006 4.51 −12.330 007 5.63 −12.323 008 4.62 −12.549 009 4.59 −12.506 010 4.64 −11.908 011 4.43 −12.275 012 4.84 −12.818 013 4.51 −12.370 014 5.76 −12.593 015 5.89 −12.395 016 4.92 −12.366 017 4.98 −12.362 018 4.62 −12.146 019 4.09 −11.855

In an embodiment there is provided a composition comprising a pharmaceutically effective amount of a compound as described previously.

In an embodiment, the nitrogen atom on the core six-membered ring is not methylated (e.g. Compound 025 is not methylated). In an embodiment, the nitrogen atom on the core six-membered ring is methylated (e.g. Compound 025 is methylated).

In an embodiment the composition comprises a dosage amount in the range of 0.05 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.1 mg to 50 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.5 mg to 25 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.5 mg to 10 mg.

In an embodiment the composition comprises a dosage amount in the range of 1 mg to 10 mg.

In an embodiment the composition comprises a dosage amount in the range of 1 mg to 8 mg.

In an embodiment the composition comprises a dosage amount in the range of 3 mg to 15 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.005 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.001 mg to 100 mg.

In an embodiment the composition comprises a dosage amount in the range of 0.0005 mg to 100 mg.

The level of the active agent can be adjusted as required by need for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.

In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous, rectal dosage, intranasal, intramuscular, or any other parenteral form.

In an embodiment the composition is formulated in a dosage form selected from: oral, transdermal, inhalable, intravenous or rectal dosage

It is advantageous to be able to deliver the active agent in different forms, for example to suit a certain patient group (e.g. the elderly) or the conditions being treated.

In an embodiment the composition is formulated in a dosage form selected from: tablet, capsule, granules, powder, free-flowing powder, inhalable powder, aerosol, nebulised, vaping, buccal, sublingual, sublabial, injectable, or suppository dosage form.

In an embodiment the powder is suitable for administration by inhalation via a medicament dispenser selected from a reservoir dry powder inhaler, a unit-dose dry powder inhaler, a pre-metered multi-dose dry powder inhaler, a nasal inhaler or a pressurized metered dose inhaler.

In an embodiment the powder comprises particles, the particles having a median diameter of less than 2000 μm, 1000 μm, 5001 μm, 250 μm, 100 μm, 50 μm, or 1 μm.

In an embodiment the powder comprises particles, the particles having a median diameter of greater than 500 μm, 250 μm, 100 μm, 50 μm, 1 μm or 0.5 μm.

In an embodiment the powder comprises particles, and wherein the powder has a particle size distribution of d10=20-60 μm, and/or d50=80-120 μm, and/or d90=130-300 μm.

The nature of the powder can be adjusted to suit need. For example, if being made for nasal inhalation, then the particles may be adjusted to be much finer than if the powder is going to be formulated into a gelatine capsule, or differently again if it is going to be compacted into a tablet.

In an embodiment the compound is in the form of a salt which is amorphous or crystalline.

In an embodiment the salt is in a polymorphic crystalline form.

In an embodiment the salt is a benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt, optionally the salt is the chloride, benzoate or fumarate salt.

In an embodiment the salt is formulated into a composition for mucosal delivery. In an embodiment, the salt is a benzoate salt.

For the salt, the dosage amount is the equivalent amount of the free base delivered when the salt is taken. So 100 mg dosage amount may for example correspond to 117 mg of a hydrochloride salt (i.e. both providing the same molar amount of the active substance). The greater mass of the salt needed is due to the larger formula weight of the hydrogen chloride salt. Similarly, for the deuterated or triturated version of the compounds of the invention (also considered within the scope of the invention), a slight increase in mass can be expected due to the increased formula weight of these isotopic compounds.

Amorphous and crystalline substances often show different chemical/physical properties, e.g. improved rate of dissolution in a solvent, or improved thermal stability. Similarly, different polymorphs may also show different and useful chemical/physical properties.

In an embodiment the composition comprises one or more pharmaceutically acceptable carriers or excipients.

In an embodiment the composition comprises one or more of: mucoadhesive enhancer, penetrating enhancer, cationic polymers, cyclodextrins, Tight Junction Modulators, enzyme inhibitors, surfactants, chelators, and polysaccharides.

In an embodiment the composition comprises one or more of: chitosan, chitosan derivatives (such as N,N,N-trimethyl chitosan (TMC), n-propyl-(QuatPropyl), n-butyl-(QuatButyl) and n-hexyl (QuatHexyl)-N,N-dimethyl chitosan, chitosan chloride), β-cyclodextrin, Clostridium perfringens enterotoxin, zonula occludens toxin (ZOT), human neutrophil elastase inhibitor (ER143), sodium taurocholate, sodium deoxycholate sodium, sodium lauryl sulphate, glycodeoxycholat, palmitic acid, palmitoleic acid, stearic acid, oleyl acid, oleyl alcohol, capric acid sodium salt, DHA, EPA, dipalmitoyl phophatidyl choline, soybean lecithin, lysophosphatidylcholine, dodecyl maltoside, tetradecyl maltoside, EDTA, lactose, cellulose, and citric acid.

In an embodiment the compound or composition defined herein above for use in a method of treatment of a human or animal subject by therapy.

In an embodiment the method of treatment is a method of treatment of:

conditions caused by dysfunctions of the central nervous system,

conditions caused by dysfunctions of the peripheral nervous system,

conditions benefiting from sleep regulation (such as insomnia),

conditions benefiting from analgesics (such as chronic pain),

migraines,

trigeminal autonomic cephalgias (such as short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting neuralgiform headaches with cranial autonomic symptoms (SUNA)),

conditions benefiting from neurogenesis (such as stroke, traumatic brain injury, Parkinson's dementia),

conditions benefiting from anti-inflammatory treatment,

depression,

anxiety,

substance use disorder,

addictive disorder,

gambling disorder,

eating disorders,

obsessive-compulsive disorders, or

body dysmorphic disorders,

optionally the condition is SUNCT and/or SUNA.

Treatment of the above conditions may be beneficially improved by taking the invention.

In an embodiment the method of treatment is a method of treatment of more than one of the above conditions, for example, the method of treatment may be a method of treatment of depression and anxiety.

In an embodiment the composition is administered one or more times a year.

In an embodiment the composition is administered one or more times a month.

In an embodiment the composition is administered one or more times a week.

In an embodiment the composition is administered one or more times a day.

In an embodiment the composition is administered at such a frequency as to avoid tachyphylaxis.

In an embodiment the composition is administered together with a complementary treatment and/or with a further active agent.

In an embodiment the further active agent is a psychedelic compound, optionally a further tryptamine.

In an embodiment the further active agent is a psychedelic compound, optionally a tryptamine.

In an embodiment the further active agent is psilocybin, psilocin or a prodrug thereof.

In an embodiment the complementary treatment is psychotherapy.

In an embodiment, there is provided a composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.

In an embodiment, there is provided a nasal inhalation composition comprising a pharmaceutically effective amount of a compound as described herein for use in a method of treatment of treatment resistant depression.

Treatment of the above conditions may be beneficially improved by taking the invention together with some complementary treatments; also these treatments may occur much less regularly than some other treatments that require daily treatments or even multiple treatments a day.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay results for compounds 018 and 019.

FIG. 2 shows serotonin (2a, 2b and 2c receptors) inositol phosphate 1 (IP₁) assay results for compounds 018 and 019.

FIG. 3 shows serotonin (2a, 2b and 2c receptors) calcium (Ca²⁺) assay results for compounds 018 and 019.

FIG. 4 shows serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assay results for compounds 018 and 019.

FIG. 5 shows serotonin 2b receptor B-arrestin assay results for compounds 018 and 019.

DETAILED DESCRIPTION OF THE INVENTION

The crystal structures of the serotonin receptor were retrieved from the Protein Data Bank (www.rcsb.org) [PDB ID: 5TVN and 6WGT for 5-HT2B and 5-HT2A respectively. Both proteins were prepared for docking of candidate ligands. Briefly, hydrogens were added, bond orders were assigned, and loops and side chains were filled. Restrain minimization was performed using Optimized Potentials for Liquid Simulations (OPLS2005) force field until the RMSD reached 0.3 Å from the initial geometry in order to improve steric clashes. Additionally, other possible receptor targets were used and prepared structurally as further indicated below.

Binding Pocket Analysis

Only two crystallographic structures are available from the Protein Data Bank of the 5-HT2A and 5-HT2B receptors in complex with (8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide which represents an active isoform of LSD. The binding pockets were analysed to determine the interaction between the receptor residues and the ligands structure. Homologies modelling was applied to determine similarities in several receptor/protein targets. Moreover the binding pocket was analysed by intrinsic dynamic Domains (IDD) methodology to further verify the residues on the receptors that most contribute to the activity of the binding site.

Ligands

Initial consideration regarding anti-inflammatory properties, vaso-constriction, vaso-dilation and psychedelic effects were considered.

Upon further analysis the scaffold, lysergic acid amide deprived of the C8 amide group was used. Analysis of key attachment points was implemented and subsequently R-groups were assigned to the initial scaffold. The R-groups were selected from a library of fragments. The compounds were filtered by Lipinski's rule of five (RO5), rapid elimination of swill (REOS) and pan assay interference compounds (PAINS 1, 2, and 3).

The resulting ligand structures were prepared for docking by identifying stereoisomers with protonation states of pH7±2.

Docking

In the binding pocket residues containing hydroxyl and thiol groups were rotated to account for some flexibility of the pocket in the first stage of rigid docking. Subsequently the best compounds were used for flexible docking in order to further simulate a physiological state of the receptors.

Molecular Dynamics Simulation

Simulations for both receptors were implemented on the basis of the top ligand binding scores. All of the simulations were carried out using the MD Desmond package. Available crystal structures were used. The receptor and ligand complexes were set up in an orthorhombic box using a buffer condition of 10 Å. The orientations of the membranes (if available) were from the Orientation of Protein in Membranes (OPM) database. Ions were neutralized for the system, salt was added at a concentration of 0.15 M NaCl, and OPLS 2005 was used for the force field. Long-range electrostatic interactions were calculated with the Ewald method using a cut-off of 9 Å for Van der Waals and Coulomb interactions. The simulation was carried out in an isothermal, isobaric ensemble (NPT) with an initial temperature of 300° K and 1 bar of pressure. The temperature followed the Nose-Hoover method and the pressure was controlled by the Martyna-Tobias-Klein protocol. The simulation was set for 200 ns and trajectories were recorded every 100 ps. The default relaxation protocol for the system was used. Representative structures were extrapolated from the simulation at 0, 100, and 200 ns.

Chemical and Other Pharmacokinetic Properties

The compounds were analysed computationally regarding suitable chemical characteristic and pharmacokinetic parameters and compared across known agonists of mainly the two serotonin receptors (5-HT2A and 2B). Several algorithms were implemented.

Identified Ergoline Analogues

The structures of selected ergoline analogues are shown in the table above and further described below:

Properties of Selected Ergoline Analogues

Various properties of selected ergoline analogues are detailed in the tables below, followed by an explanation of the properties:

Number Formula MW Heavy atoms 001 C11H13N2 173.23 13 002 C20H27N4O2 355.45 26 003 C22H23N4O 359.44 27 004 C22H29N4O2 381.49 28 005 C24H27N4O3S 451.56 32 006 C21H29N4O2 369.48 27 007 C23H29N4O2 393.5 29 008 C22H28N3O3 382.48 28 009 C23H25N4O3S 437.53 31 010 C21H29N4O3S 417.54 29 011 C24H25N4O2 401.48 30 012 C22H32N5O3S 446.59 31 013 C21H29N4O2 369.48 27 014 C24H31N4O2 407.53 30 015 C25H33N4O2 421.56 31 016 C22H31N4O4S 447.57 31 017 C24H36N4O2 412.57 30 018 C24H34N3O 380.55 28 019 C19H24N3O 310.41 23

Number Aromatic heavy atoms Csp3 Rotatable bonds 001 9 0.27 1 002 9 0.45 6 003 15 0.27 3 004 9 0.5 4 005 15 0.29 5 006 9 0.48 7 007 9 0.52 3 008 9 0.5 4 009 15 0.26 5 010 9 0.48 7 011 15 0.25 5 012 9 0.5 8 013 9 0.48 6 014 9 0.54 4 015 9 0.56 4 016 9 0.5 8 017 9 0.54 8 018 9 0.54 7 019 9 0.42 3

Number H-bond acceptors H-bond donors MR 001 0 2 54.73 002 3 4 107.22 003 2 2 112.66 004 3 3 114.65 005 4 2 129.16 006 3 3 111.95 007 3 2 121.35 008 3 2 112.93 009 4 3 124.26 010 4 3 119.83 011 2 3 123.06 012 5 4 127.44 013 3 4 112.03 014 3 2 126.16 015 3 2 130.96 016 5 3 125.73 017 2 3 127.73 018 1 2 122.49 019 1 3 98.36

Number TPSA LOGP XLOGP3 001 43.43 1.64 1.36 002 72.8 2.73 1.65 003 53.43 2.55 2.7 004 61.8 2.63 2.39 005 86.3 3.14 3.26 006 61.8 3.1 2.19 007 53.01 3.04 2.7 008 59 2.88 2.67 009 95.09 2.59 3.07 010 95.09 2.61 1.71 011 69.64 2.85 3.94 012 107.12 2.16 1.88 013 72.8 2.85 2.1 014 53.01 3.15 3.14 015 53.01 3.05 3.49 016 104.32 2.28 2.17 017 54.21 3.9 3.46 018 40.54 3.46 4.81 019 49.33 2.71 2.83

Number WLOGP MLOGP Consensus Log P 001 1.27 −2.13 0.91 002 −0.41 −2.18 0.68 003 1.3 −1.7 1.52 004 0.38 −1.74 1.13 005 2.01 −1.41 1.67 006 0.24 −1.96 1.15 007 0.1 −1.53 1.21 008 0.81 −1.74 1.39 009 1.67 −1.62 1.42 010 0.72 −2.1 0.89 011 1.74 −0.94 2.01 012 0.61 −2.67 0.59 013 −0.03 −1.96 0.96 014 0.48 −1.32 1.51 015 0.87 −1.11 1.73 016 1.04 −2.67 0.82 017 −0.06 −5 1.01 018 2.67 −0.49 2.98 019 0.76 −1.58 1.53

ESOL Solubility ESOL Solubility Number ESOL Log S (mg/ml) (mol/l) 001 −2.22 1.05 0.00607 002 −2.94 0.405 0.00114 003 −3.98 0.0374 0.000104 004 −3.68 0.0788 0.000207 005 −4.71 0.0088 0.0000195 006 −3.3 0.187 0.000507 007 −4.01 0.0382 0.0000972 008 −3.87 0.0519 0.000136 009 −4.51 0.0134 0.0000306 010 −3.27 0.222 0.000532 011 −4.85 0.00565 0.0000141 012 −3.48 0.148 0.000331 013 −3.3 0.183 0.000496 014 −4.3 0.0203 0.0000498 015 −4.6 0.0105 0.0000249 016 −3.67 0.0959 0.000214 017 −4.27 0.0221 0.0000535 018 −5.01 0.00376 0.00000987 019 −3.64 0.0713 0.00023

Solubility Class (II-method) Solubility Number (ESOL) Log S (mg/ml) 001 Soluble −1.87 2.31 002 Soluble −2.79 0.574 003 Soluble −3.48 0.12 004 Soluble −3.33 0.179 005 Moderately soluble −4.75 0.0081 006 Soluble −3.12 0.279 007 Moderately soluble −3.47 0.135 008 Soluble −3.56 0.105 009 Moderately soluble −4.73 0.00808 010 Soluble −3.32 0.199 011 Moderately soluble −5.1 0.00317 012 Soluble −3.75 0.0791 013 Soluble −3.26 0.203 014 Moderately soluble −3.92 0.0487 015 Moderately soluble −4.29 0.0218 016 Soluble −3.99 0.0454 017 Moderately soluble −4.28 0.0216 018 Moderately soluble −5.39 0.00154 019 Soluble −3.52 0.0929

Number Solubility (mol/l) II method Class Pgp substrate 001 0.0134 Very soluble No 002 0.00161 Soluble Yes 003 0.000335 Soluble Yes 004 0.000469 Soluble Yes 005 0.0000179 Moderately soluble Yes 006 0.000756 Soluble Yes 007 0.000342 Soluble Yes 008 0.000275 Soluble Yes 009 0.0000185 Moderately soluble Yes 010 0.000476 Soluble Yes 011 0.0000079 Moderately soluble Yes 012 0.000177 Soluble Yes 013 0.000551 Soluble Yes 014 0.000119 Soluble No 015 0.0000518 Moderately soluble Yes 016 0.000101 Soluble Yes 017 0.0000525 Moderately soluble Yes 018 0.00000404 Moderately soluble Yes 019 0.000299 Soluble Yes

CYP1A2 CYP2C19 CYP2C9 Number inhibitor inhibitor inhibitor 001 Yes No No 002 No No No 003 Yes No No 004 No No No 005 No No Yes 006 No No No 007 No No No 008 No No No 009 No No Yes 010 No No No 011 No Yes Yes 012 No No No 013 No No No 014 No No No 015 No No No 016 No No No 017 No No No 018 No Yes Yes 019 No No No

CYP2D6 CYP3A4 Number inhibitor inhibitor log Kp (cm/s) 001 No No −6.39 002 No No −7.3 003 No No −6.58 004 No No −6.93 005 No Yes −6.74 006 No No −7 007 Yes No −6.78 008 No No −6.74 009 No No −6.79 010 No No −7.63 011 No No −5.95 012 No No −7.69 013 No No −7.06 014 Yes No −6.56 015 Yes No −6.39 016 No No −7.49 017 No No −6.36 018 No No −5.21 019 No No −6.18

Number Lipinski #violations Ghose violations Veber violations 001 0 0 0 002 0 1 0 003 0 0 0 004 0 0 0 005 0 0 0 006 0 0 0 007 0 0 0 008 0 0 0 009 0 0 0 010 0 0 0 011 0 0 0 012 0 0 0 013 0 0 0 014 0 0 0 015 0 1 0 016 0 0 0 017 0 0 0 018 0 0 0 019 0 0 0

Bioavailability Number Egan violations Muegge violations Score 001 0 1 0.55 002 0 0 0.55 003 0 0 0.55 004 0 0 0.55 005 0 0 0.55 006 0 0 0.55 007 0 0 0.55 008 0 0 0.55 009 0 0 0.55 010 0 0 0.55 011 0 0 0.55 012 0 0 0.55 013 0 0 0.55 014 0 0 0.55 015 0 0 0.55 016 0 0 0.55 017 0 0 0.55 018 0 0 0.55 019 0 0 0.55

Number PAINS alerts Brenk alerts Leadlikeness violations 001 0 0 1 002 0 0 1 003 0 0 1 004 0 0 1 005 0 0 1 006 0 0 1 007 0 0 1 008 0 1 1 009 0 0 1 010 0 0 1 011 0 0 2 012 0 0 2 013 0 0 1 014 0 0 1 015 0 0 1 016 0 1 2 017 0 1 2 018 0 0 2 019 0 0 0

Number Synthetic Accessibility Docking scores (Kcal/mol) 001 2.35 −8.579 002 4.39 −13.446 003 4.19 −12.761 004 4.55 −12.399 005 4.72 −12.957 006 4.51 −12.330 007 5.63 −12.323 008 4.62 −12.549 009 4.59 −12.506 010 4.64 −11.908 011 4.43 −12.275 012 4.84 −12.818 013 4.51 −12.370 014 5.76 −12.593 015 5.89 −12.395 016 4.92 −12.366 017 4.98 −12.362 018 4.62 −12.146 019 4.09 −11.855

Naming and Strings

IUPAC name=compound name

Smile=Smile naming convention of compound

Formula=Chemical formula compound

Physiochemical Properties

MW=Molecular weight

Heavy atoms=Atoms with significantly higher atomic scattering factor than the others present

Aromatic heavy atoms=As above referring to the ring structures

Csp3=the ratio of sp3 hybridized carbons over the total carbon count of the molecule (> or equal to 0.25)

Rotable bonds=Bonds in the molecule that can rotate

H-Bonds acceptor=Bonds that can accept hydrogen ion

H-Bonds doner=Bonds that can donate hydrogen ion

MR=Molecular refractivity

TPSA=topological polar surface area

Lipophilicity

LOG P=partition coefficient for ionisable compounds. An approximation implemented by CHARMM version c36 (Chemistry at Harvard Macromolecular Mechanics)

X LOG P=another atomistic method with correction factors from: Cheng, T. et al. Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge. J Chem Inf. Model 47, 2140-2148 (2007).

W LOG P=is another Log P using the Wildman method described in: Wildman, S. A. & Crippen, G. M. Prediction of Physicochemical Parameters by Atomic Contributions. J. Chem. Inf. Model. 39, 868-873 (1999).

M LOG P=Moriguchi topological method for partition coefficient. Moriguchi, I., Shuichi, H., Liu, Q., Nakagome, I. & Matsushita, Y. Simple Method of Calculating Octanol/Water Partition Coefficient. Chem. Pharm. Bull. 40, 127-130 (1992).

General Log p=In order to increase the accuracy of the Log P o/W the above methods were used and a general estimation of these values was condensed in “General Log P” column

Solubility

ESOL Log S=Aqueous solubility by ESOL method: Delaney, J. S. ESOL: Estimating Aqueous Solubility Directly from Molecular Structure. J. Chem. Inf. Model. 44, 1000-1005 (2004)

ESOL Solubility (mg/ml)=quantification of solubility by SwissADME

ESOL Solubility (mol/1)=as above

Solubility class for ESOL method=solubility in aqueous solution

II methods Log S=Solubility method based on: Ali, J., Camilleri, P., Brown, M. B., Hutt, A. J. & Kirton, S. B. Revisiting the general solubility equation: in silico prediction of aqueous solubility incorporating the effect of topographical polar surface area. J. Chem. Inf. Model. 52, 420-428 (2012).

Pharmacokinetics

Pgp substrate=P glycoprotein, this describes if the compound is a substrate of glycoprotein associated with the permeability of biological membranes.

The below subfamilies of the cytochrome P450 determine drug elimination and metabolism in association with Pgp data: CYP1A2 inhibitor, CYP2C19 inhibitor, CYP2C9 inhibitor, CYP2D6 inhibitor, CYP3A4 inhibitor,

Drug-Likeness

Lipinski violations

Ghose violations

Veber violations

Egan violations

Muegge violations

Bioavailability Score (The Abbot Bioavailability Score)

Synthesis

“PAINS (Pan-assay interference compounds)=Baell, J. B. & Holloway, G. A. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719-2740 (2010).”

“Brenk alerts=Brenk, R. et al. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem 3, 435-444 (2008).”

“Lead likeness violations=based on: Teague, S., Davis, A., Leeson, P. & Oprea, T. The Design of Lead like Combinatorial Libraries. Angew. Chem. Int. Ed. Engl. 38, 3743-3748 (1999).”

“Synthetic Accessibility=based on two papers: Fukunishi, Y., Kurosawa, T., Mikami, Y. & Nakamura, H. Prediction of synthetic accessibility based on commercially available compound databases. J Chem Inf Model 54, 3259-3267 (2014).

Ertl, P. & Schuffenhauer, A. Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. J. Cheminform. 1, 8 (2009). From 1 to 10 with 1 easy and 10 complex”

Docking Scores (Kcal/mol)

Scores are reported for docking to the target, the highest negative number indicates a better binding pose of the ligand in the receptor (5-HT2A) (similar scores are related to the 5-HT2B).

Abbreviations

-   5-HT #=5-hydroxytryptamine receptor # HH1R=Histamine H1 receptor -   A #AR=Alpha-# adrenergic receptor M.Rec=Membrane receptor -   B #AR=Beta-# adrenergic receptor MAPTau=Microtubule-associated     protein tau -   CP450 #=Cytochrome P450 # MBLP #=Muscleblind-like protein # -   CXCCRT3=C—X—C chemokine receptor type 3 Na-Dep=Sodium-dependent -   D(#)DR=D(#)DR Trans.=Transporter -   D(#)DR=D(#) dopamine receptor Unc=Unclassified -   Enz=Enzyme where #=a number

Compound/Target Data

Further Information Regarding Targets Screened

The table below details the range of targets that selected ergoline analogues were screened against and the results.

Number Number of sim. of sim. Compound Uniprot Gene ChEMBL By cmpds cmpds Target Number Target ID Code ID Homology Probability (3D) (2D) Class 001 5HTR2A P28223 HTR2A 224 No 1 76 193 M. Rec 5HTR2C P28335 HTR2C 225 No 1 71 151 M. Rec 5HTR2B P41595 HTR2B 1833 No 1 71 151 M. Rec 5HTR1A P08908 HTR1A 214 Yes 0.74 12 528 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.74 17 444 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.74 19 542 M. Rec 5HTR1E P28566 HTR1E 2182 Yes 0.74 10 425 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.74 10 425 M. Rec 5HTR6 P50406 HTR6 3371 No 0.74 6 184 M. Rec MBLP#1 Q9NR56 MBNL1 1293317 No 0.74 1 19 Unc MBLP#2 Q5VZF2 MBNL2 Yes 0.74 1 19 Unc MBLP#3 Q9NUKO MBNL3 Yes 0.74 1 19 Unc Na-Dep P23975 SLC6A2 222 Yes 0.64 18 194 Trans. noradrenaline Trans. Na-Dep P31645 SLC6A4 228 No 0.64 35 262 Trans. serotonin Trans. Na-Dep Q01959 SLC6A3 238 No 0.64 18 194 Trans. dopamine Trans. 002 D(2)DR P14416 DRD2 217 No 0.88 383 93 M. Rec D(1A)DR P21728 DRD1 2056 No 0.88 33 20 M. Rec D(4)DR P21917 DRD4 219 No 0.88 182 17 M. Rec D(1B)DR P21918 DRD5 1850 No 0.88 27 20 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.88 75 86 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.88 225 111 M. Rec 5HTR2A P28223 HTR2A 224 No 0.88 166 34 M. Rec 5HTR2C P28335 HTR2C 225 No 0.88 111 23 M. Rec D(3)DR P35462 DRD3 234 No 0.88 217 40 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.88 111 23 M. Rec 5HTR6 P50406 HTR6 3371 No 0.88 33 52 M. Rec B2AR P07550 ADRB2 210 No 0.87 439 7 M. Rec B1AR P08588 ADRB1 213 No 0.87 444 7 M. Rec B3AR P13945 ADRB3 246 Yes 0.87 427 7 M. Rec A2aAR P08913 ADRA2A 1867 No 0.87 39 10 M. Rec 003 D(2)DR P14416 DRD2 217 No 0.89 2724 112 M. Rec D(3)DR P35462 DRD3 234 No 0.89 1579 46 M. Rec 5HTR1A P08908 HTR1A 214 No 0.87 1288 107 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.87 1358 117 M. Rec D(1A)DR P21728 DRD1 2056 No 0.87 252 20 M. Rec D(1B)DR P21918 DRD5 1850 No 0.87 181 20 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.86 549 86 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.86 442 72 M. Rec 5HTR1F P30939 HTR1F 1805 No 0.86 442 72 M. Rec 5HTR6 P50406 HTR6 3371 No 0.85 484 54 M. Rec D(4)DR P21917 DRD4 219 No 0.85 1030 17 M. Rec 5HTR2A P28223 HTR2A 224 No 0.85 1067 35 M. Rec 5HTR7 P34969 HTR7 3155 No 0.85 411 19 M. Rec 5HTR2C P28335 HTR2C 225 No 0.85 636 24 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.85 636 24 M. Rec 004 5HTR7 P34969 HTR7 3155 No 0.84 52 14 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.84 8 9 M. Rec 5HTR6 P50406 HTR6 3371 No 0.84 65 39 M. Rec D(2)DR P14416 DRD2 217 No 0.84 621 82 M. Rec D(1A)DR P21728 DRD1 2056 No 0.84 48 19 M. Rec D(4)DR P21917 DRD4 219 No 0.84 311 16 M. Rec D(1B)DR P21918 DRD5 1850 No 0.84 40 19 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.84 132 84 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.84 342 99 M. Rec 5HTR2A P28223 HTR2A 224 No 0.84 285 32 M. Rec 5HTR2C P28335 HTR2C 225 No 0.84 217 21 M. Rec D(3)DR P35462 DRD3 234 No 0.84 383 37 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.84 217 21 M. Rec 5HTR1A P08908 HTR1A 214 No 0.83 333 89 M. Rec A2aAR P08913 ADRA2A 1867 No 0.81 75 9 M. Rec 005 D(2)DR P14416 DRD2 217 No 0.77 1437 60 M. Rec D(4)DR P21917 DRD4 219 No 0.77 549 18 M. Rec D(3)DR P35462 DRD3 234 No 0.77 850 37 M. Rec 5HTR1A P08908 HTR1A 214 No 0.75 791 56 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.75 305 52 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.75 847 61 M. Rec 5HTR2A P28223 HTR2A 224 No 0.75 599 27 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.75 236 45 M. Rec 5HTR1F P30939 HTR1F 1805 No 0.75 236 45 M. Rec 5HTR7 P34969 HTR7 3155 No 0.75 255 12 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.75 45 9 M. Rec 5HTR6 P50406 HTR6 3371 No 0.75 417 87 M. Rec 5HTR2C P28335 HTR2C 225 No 0.75 368 15 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.75 368 15 M. Rec B2AR P07550 ADRB2 210 No 0.73 19 7 M. Rec 006 5HT1IA P08908 HTR1A 214 No 0.88 338 102 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.88 346 112 M. Rec 5HTR2A P28223 HTR2A 224 No 0.86 299 33 M. Rec 5HTR2C P28335 HTR2C 225 No 0.86 230 22 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.86 230 22 M. Rec 5HTR6 P50406 HTR6 3371 No 0.86 69 48 M. Rec D(2)DR P14416 DRD2 217 No 0.86 610 92 M. Rec D(1A)DR P21728 DRD1 2056 No 0.86 46 20 M. Rec D(4)DR P21917 DRD4 219 No 0.86 315 17 M. Rec D(1B)DR P21918 DRD5 1850 No 0.86 40 20 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.86 131 85 M. Rec 5HTR7 P34969 HTR7 3155 No 0.86 56 16 M. Rec D(3)DR P35462 DRD3 234 No 0.86 377 38 M. Rec B2AR P07550 ADRB2 210 No 0.85 536 7 M. Rec B1AR P08588 ADRB1 213 No 0.85 539 7 M. Rec 007 D(2)DR P14416 DRD2 217 No 0.77 621 74 M. Rec D(1A)DR P21728 DRD1 2056 No 0.77 50 18 M. Rec D(4)DR P21917 DRD4 219 Yes 0.77 334 15 M. Rec D(3)DR P35462 DRD3 234 No 0.77 400 36 M. Rec 5HTR6 P50406 HTR6 3371 No 0.75 65 26 M. Rec 5HTR2A P28223 HTR2A 224 No 0.75 309 26 M. Rec D(1B)DR P21918 DRD5 1850 No 0.74 44 18 M. Rec 5HTR2C P28335 HTR2C 225 No 0.74 237 15 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.74 237 15 M. Rec AZaAR P08913 ADRA2A 1867 No 0.72 84 8 M. Rec A2BAR P18089 ADRA2B 1942 No 0.72 84 8 M. Rec A2CAR P18825 ADRA2C 1916 Yes 0.72 84 8 M. Rec MAPTau P10636 MAPT 1293224 No 0.72 307 9 Unc HH1R P35367 HRH1 231 No 0.72 94 5 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.72 116 73 M. Rec 008 D(2)DR P14416 DRD2 217 No 0.79 539 65 M. Rec 5HTR1A P08908 HTR1A 214 No 0.77 301 76 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.77 310 86 M. Rec D(4)DR P21917 DRD4 219 No 0.75 274 15 M. Rec D(3)DR P35462 DRD3 234 No 0.75 324 36 M. Rec 5HTR2A P28223 HTR2A 224 No 0.75 269 29 M. Rec 5HTR2C P28335 HTR2C 225 No 0.75 205 18 M. Rec HH1R P35367 HRH1 231 No 0.75 99 5 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.75 205 18 M. Rec B2AR P07550 ADRB2 210 No 0.75 473 7 M. Rec B1AR P08588 ADRB1 213 No 0.75 475 7 M. Rec B3AR P13945 ADRB3 246 No 0.75 455 7 M. Rec D(1A)DR P21728 DRD1 2056 No 0.75 38 18 M. Rec D(1B)DR P21918 DRD5 1850 No 0.75 33 18 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.75 100 77 M. Rec 009 5HTR2A P28223 HTR2A 224 No 0.83 773 28 M. Rec D(2)DR P14416 DRD2 217 No 0.83 1942 74 M. Rec D(4)DR P21917 DRD4 219 No 0.83 721 18 M. Rec D(3)DR P35462 DRD3 234 No 0.83 1145 38 M. Rec 5HTR1A P08908 HTR1A 214 No 0.8 1076 68 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.8 1130 76 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.8 407 65 M. Rec 5HTR2C P28335 HTR2C 225 No 0.8 478 16 M. Rec 5HTR1E P28566 HTR1IE 2182 No 0.8 335 54 M. Rec 5HTR1F P30939 HTR1F 1805 No 0.8 335 54 M. Rec 5HTR7 P34969 HTR7 3155 No 0.8 310 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.8 478 16 M. Rec 5HTR6 P50406 HTR6 3371 No 0.8 568 69 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.8 52 10 M. Rec D(1A)DR P21728 DRD1 2056 No 0.78 191 18 M. Rec 010 5HTR6 P50406 HTR6 3371 No 0.82 383 55 M. Rec D(4)DR P21917 DRD4 219 No 0.82 950 16 M. Rec D(2)DR P14416 DRD2 217 No 0.8 2423 73 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.8 487 74 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.8 1283 86 M. Rec 5HTR2A P28223 HTR2A 224 No 0.8 959 32 M. Rec 5HTR7 P34969 HTR7 3155 No 0.8 465 14 M. Rec 5HTR1A P08908 HTR1A 214 No 0.8 1246 76 M. Rec D(1A)DR P21728 DRD1 2056 No 0.8 189 19 M. Rec D(1B)DR P21918 DRD5 1850 No 0.8 145 19 M. Rec 5HTR2C P28335 HTR2C 225 No 0.8 575 21 M. Rec D(3)DR P35462 DRD3 234 No 0.8 1516 37 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.8 575 21 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.79 419 60 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.79 419 60 M. Rec 011 5HTR1A P08908 HTR1A 214 No 0.91 1137 78 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.91 1194 88 M. Rec 5HTR6 P50406 HTR6 3371 No 0.9 361 44 M. Rec D(2)DR P14416 DRD2 217 No 0.9 2285 86 M. Rec D(3)DR P35462 DRD3 234 No 0.9 1325 36 M. Rec D(4)DR P21917 DRD4 219 No 0.89 823 16 M. Rec 5HTR2A P28223 HTR2A 224 No 0.89 803 30 M. Rec D(1A)DR P21728 DRD1 2056 No 0.89 239 19 M. Rec D(1B)DR P21918 DRD5 1850 No 0.89 181 19 M. Rec 5HTR2C P28335 HTR2C 225 Yes 0.88 469 19 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.88 469 19 M. Rec A2aAR P08913 ADRA2A 1867 No 0.88 54 9 M. Rec A2BAR P18089 ADRA2B 1942 Yes 0.88 55 9 M. Rec A2CAR P18825 ADRA2C 1916 No 0.88 54 9 M. Rec CXCCRT3 P49682 CXCR3 4441 No 0.86 90 63 M. Rec 012 5HTR6 P50406 HTR6 3371 No 0.84 483 39 M. Rec 5HTR1A P08908 HTR1A 214 No 0.83 1292 68 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.83 522 69 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.83 1337 77 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.83 441 57 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.83 441 57 M. Rec 5HTR2A P28223 HTR2A 224 No 0.8 936 29 M. Rec D(2)DR P14416 DRD2 217 No 0.78 2317 74 M. Rec D(4)DR P21917 DRD4 219 No 0.78 909 15 M. Rec D(3)DR P35462 DRD3 234 No 0.78 1434 36 M. Rec 5HTR2C P28335 HTR2C 225 No 0.78 563 18 M. Rec 5HTR7 P34969 HTR7 3155 No 0.78 472 12 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.78 563 18 M. Rec D(1A)DR P21728 DRD1 2056 No 0.78 173 18 M. Rec D(1B)DR P21918 DRD5 1850 No 0.78 128 18 M. Rec 013 D(2)DR P14416 DRD2 217 No 0.9 430 95 M. Rec D(1A)DR P21728 DRD1 2056 No 0.9 36 20 M. Rec D(4)DR P21917 DRD4 219 No 0.9 235 17 M. Rec D(1B)DR P21918 DRD5 1850 No 0.9 32 20 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.9 90 84 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.9 274 111 M. Rec 5HTR2A P28223 HTR2A 224 No 0.9 207 33 M. Rec 5HTR2C P28335 HTR2C 225 No 0.9 150 22 M. Rec D(3)DR P35462 DRD3 234 No 0.9 262 38 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.9 150 22 M. Rec 5HTR6 P50406 HTR6 3371 No 0.9 46 57 M. Rec 5HTR7 P34969 HTR7 3155 No 0.89 29 16 M. Rec 5HTR1A P08908 HTR1A 214 No 0.88 267 101 M. Rec AZaAR P08913 ADRA2A 1867 No 0.88 52 10 M. Rec A2BAR P18089 ADRA2B 1942 No 0.88 52 10 M. Rec 014 5HTR1B P28222 HTR1B 1898 Yes 0.75 365 78 M. Rec D(2)DR P14416 DRD2 217 No 0.74 631 57 M. Rec D(1A)DR P21728 DRD1 2056 No 0.74 53 18 M. Rec D(4)DR P21917 DRD4 219 Yes 0.74 350 15 M. Rec D(3)DR P35462 DRD3 234 No 0.74 413 33 M. Rec 5HTR2A P28223 HTR2A 224 No 0.74 333 25 M. Rec 5HTR2C P28335 HTR2C 225 No 0.74 259 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.74 259 14 M. Rec 5HTR6 P50406 HTR6 3371 No 0.72 78 19 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.72 118 61 M. Rec 5HTR1A P08908 HTR1A 214 No 0.72 358 73 M. Rec CP4502D6 P10635 CYP2D6 289 No 0.72 23 2 Enz CP4502J2 P51589 CYP2J2 3491 No 0.72 23 2 Enz A2aAR P08913 ADRA2A 1867 No 0.72 91 8 M. Rec MAPTau P10636 MAPT 1293224 No 0.72 348 8 Unc 015 CP4502D6 P10635 CYP2D6 289 No 0.78 22 2 Enz CP4502J2 P51589 CYP2J2 3491 No 0.78 22 2 Enz MAPTau P10636 MAPT 1293224 No 0.77 268 9 Unc D(4)DR P21917 DRD4 219 No 0.77 311 15 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 314 25 M. Rec 5HTR2C P28335 HTR2C 225 No 0.77 249 14 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.77 249 14 M. Rec MBLP#1 Q9NR56 MBNL1 1293317 No 0.75 227 3 Unc MBLP#2 Q5VZF2 MBNL2 Yes 0.75 227 3 Unc MBLP#3 Q.9NUK0 MBNL3 Yes 0.75 227 3 Unc 5HTR6 P50406 HTR6 3371 No 0.75 82 19 M. Rec D(2)DR P14416 DRD2 217 No 0.73 564 57 M. Rec D(1A)DR P21728 DRD1 2056 No 0.73 49 18 M. Rec D(1B)DR P21918 DRD5 1850 Yes 0.73 42 18 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.73 113 58 M. Rec 016 5HTR1A P08908 HTR1A 214 No 0.8 1056 43 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.8 385 45 M. Rec 5HTR1B P28222 HTR1B 1898 No 0.8 1103 50 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.8 314 36 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.8 314 36 M. Rec D(2)DR P14416 DRD2 217 No 0.78 2111 59 M. Rec D(1A)DR P21728 DRD1 2056 Yes 0.78 129 18 M. Rec D(4)DR P21917 DRD4 219 No 0.78 718 15 M. Rec D(3)DR P35462 DRD3 234 No 0.78 1173 34 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 840 26 M. Rec 5HTR7 P34969 HTR7 3155 No 0.75 367 10 M. Rec 5HTR2C P28335 HTR2C 225 No 0.71 515 15 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.71 515 15 M. Rec 5HTR6 P50406 HTR6 3371 No 0.71 287 35 M. Rec D(1B)DR P21918 DRD5 1850 No 0.69 83 18 M. Rec 017 5HTR1A P08908 HTR1A 214 No 0.8 735 88 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.8 781 98 M. Rec D(2)DR P14416 DRD2 217 No 0.77 1408 76 M. Rec 5HTR2A P28223 HTR2A 224 No 0.77 563 30 M. Rec 5HTR2C P28335 HTR2C 225 No 0.77 342 19 M. Rec D(3)DR P35462 DRD3 234 No 0.77 752 37 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.77 342 19 M. Rec 5HTR6 P50406 HTR6 3371 No 0.75 256 37 M. Rec MAPTau P10636 MAPT 1293224 No 0.75 398 12 Unc D(4)DR P21917 DRD4 219 No 0.75 469 16 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.75 263 84 M. Rec 5HTR7 P34969 HTR7 3155 No 0.75 240 13 M. Rec 5HTR5A P47898 HTR5A 3426 No 0.75 23 9 M. Rec 5HTR1E P28566 HTR1E 2182 No 0.75 203 70 M. Rec 5HTR1F P30939 HTR1F 1805 Yes 0.75 203 70 M. Rec 018 5HTR2A P28223 HTR2A 224 Yes 0.94 384 39 M. Rec D(2)DR P14416 DRD2 217 No 0.94 823 160 M. Rec D(4)DR P21917 DRD4 219 No 0.94 340 23 M. Rec D(3)DR P35462 DRD3 234 No 0.94 488 80 M. Rec D(1A)DR P21728 DRD1 2056 No 0.93 77 20 M. Rec D(1B)DR P21918 DRD5 1850 No 0.93 60 20 M. Rec 5HTR2C P28335 HTR2C 225 No 0.92 208 26 M. Rec 5HTR7 P34969 HTR7 3155 No 0.92 143 21 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.92 208 26 M. Rec 5HTR1A P08908 HTR1A 214 No 0.92 420 161 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.92 442 169 M. Rec B2AR P07550 ADRB2 210 No 0.92 14 7 M. Rec B1AR P08588 ADRB1 213 No 0.92 14 7 M. Rec B3AR P13945 ADRB3 246 Yes 0.92 14 7 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.92 179 127 M. Rec 019 5HTR2A P28223 HTR2A 224 No 0.93 635 36 M. Rec D(2)DR P14416 DRD2 217 No 0.92 1559 132 M. Rec 5HTR2C P28335 HTR2C 225 No 0.92 392 24 M. Rec 5HTR7 P34969 HTR7 3155 No 0.92 228 19 M. Rec 5HTR2B P41595 HTR2B 1833 No 0.92 392 24 M. Rec B2AR P07550 ADRB2 210 No 0.91 18 7 M. Rec Bl AR P08588 ADRB1 213 No 0.91 19 7 M. Rec 5HTR1A P08908 HTR1A 214 No 0.91 801 133 M. Rec B3AR P13945 ADRB3 246 Yes 0.91 18 7 M. Rec D(1A)DR P21728 DRD1 2056 No 0.91 194 20 M. Rec D(4)DR P21917 DRD4 219 No 0.91 632 23 M. Rec D(1B)DR P21918 DRD5 1850 No 0.91 160 20 M. Rec 5HTR1D P28221 HTR1D 1983 No 0.91 315 101 M. Rec 5HTR1B P28222 HTR1B 1898 Yes 0.91 841 141 M. Rec HH1R P35367 HRH1 231 No 0.91 132 6 M. Rec

Synthetic Routes

Salt formation is undertaken thereafter in the above routes as necessary, e.g. to give the benzoate, fumarate, citrate, acetate, succinate, halide, fluoride, chloride, bromide, iodide, oxalate, or triflate salt. For example, the addition of hydrogen chloride would provide the chloride salt and benzoic acid would give the benzoate salt.

In an embodiment, there is provided a method of synthesis of any of the herein described compounds. In an embodiment, there is provided a method of synthesis of compound 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018 or 019 as herein disclosed.

Further Characterisation of Compounds 018 and 019

cAMP

Compounds 018 (above, left) and 019 (above, right) were assayed using a serotonin (1a, 1b, 2a, 2c and 7 receptors) cAMP assay, provided by Multispan. The reference used was 10 μM forskolin (a cAMP activator) to calculate the percentage relative response, serotonin was used as the control. The results can be seen in FIG. 1 . Compound 019 was active against in all other receptor assays. The results indicate that compound 019 stimulates the 5HT_(2a)R leading to downstream activation of cAMP, although the curve response seems atypical compared to the serotonin control.

IP₁

Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2c receptors) inositol phosphate 1(IP₁) assay, provided by Multispan. The reference used was 1 μM serotonin to calculate the percentage relative response. The results can be seen in FIG. 2 . Both compounds appear to some activity against all three target receptors in this assay. This may imply that the compounds do not activate any Gagni pathway.

Ca²⁺

Compounds 018 and 019 were assayed using a serotonin (2a, 2b and 2c receptors) calcium (Ca²⁺) assay, provided by Multispan. The reference used was 10 μM serotonin to calculate the percentage relative response in relative light units (RLU). The results can be seen in FIG. 3 . Both compounds have some activity against the 2a and 2c receptors.

B-Arrestin

Compounds 018 and 019 were assayed using a serotonin (1a, 1b, 2a and 2c receptors) B-arrestin assay, provided by DiscoverX. The reference used was 10 μM serotonin to calculate the percentage relative response. The results can be seen in FIG. 4 . In general, both compounds exhibited some activity in comparison to serotonin.

The compounds were also assayed in a serotonin 2b receptor B-arrestin assay, the results of which can be seen in FIG. 5 .

Reagent Information

B-Arrestin:

HTR1A PathHunter® eXpress HTR1A CHO-K1 β-Arrestin GPCR Assay 93-0696E2CP0M

200 dp (2×96-well)

HTR1B PathHunter® eXpress HTR1B U2OS β-Arrestin GPCR Assay 93-0697E3CP6M

200 dp (2×96-well)

HTR2A PathHunter® eXpress HTR2A U2OS β-Arrestin GPCR Assay 93-0401E3CP19M

200 dp (2×96-well)

HTR2C PathHunter® eXpress HTR2C U2OS β-Arrestin GPCR Assay 93-0289E3CP3M

200 dp (2×96-well)

Multispan β-arrestin assay with CHO-K1-5HT_(2b)R cells—Catalog C1350-1a

Homogeneous Time Resolved Fluorescence (HTRF) and Calcium:

IP-One Gq kit—cisbio—cat. No. 62IPAPEB

cAMP Gs dynamic kit—cisbio—cat. No. 62AM4PEC

FLIPR calcium 6 assay explorer kit—VWR—cat. No. MLDVR8190

Cells Used in HTRF and Calcium Assays:

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1A Receptor, Catalog DC1319a

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT1B Receptor, Catalog DC1320a

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5HT1B Receptor, Catalog DC1320a

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2A Receptor, Catalog DC1324-1

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2B Receptor, Catalog DC1325-1

MULTISCREEN™ CHO-K1 Cell Line Stably Expressing Human 5-HT2C Receptor, Catalog DC1326-1

MULTISCREEN™ HEK293T Cell Line Stably Expressing Human 5-HT7 Receptor, Catalog DC1334

For the B-arrestin assays the cells came with the kits apart from the 2b receptor assay (Valiscreen serotonin 5HT-2B (human) cell line—ES-314-C, Perkin Elmer). 

1-44. (canceled)
 45. A method of treatment of a subject, comprising administering a compound or pharmaceutically acceptable salt thereof to the subject, wherein the compound is selected from:


46. The method according to claim 45, wherein the subject is a human.
 47. The method according to claim 45, wherein the subject has depression.
 48. The method according to claim 47, wherein the subject has treatment-resistant depression.
 49. The method according to claim 47, wherein the compound or pharmaceutically acceptable salt thereof is administered together with a complementary treatment, and the complementary treatment is psychotherapy.
 50. The method according to claim 45, wherein the subject has anxiety.
 51. The method according to claim 45, wherein the subject has an inflammatory condition.
 52. The method according to claim 45, wherein the subject has a pain condition.
 53. The method according to claim 52, wherein the subject has a chronic pain condition.
 54. The method according to claim 45, wherein the compound or pharmaceutically acceptable salt thereof is administered one or more times a month.
 55. The method according to claim 45, wherein the compound or pharmaceutically acceptable salt thereof is administered orally, buccally, sublingually, transdermally, sublabially, by inhalation, intravenously, or rectally.
 56. The method according to claim 45, wherein the compound or pharmaceutically acceptable salt thereof is administered as a composition in a dosage form selected from a tablet, a capsule, granules, powder, an aerosol, an injectable liquid, or a suppository.
 57. The method according to claim 45, wherein the compound or pharmaceutically acceptable salt thereof is administered together with a complementary treatment, a further active agent, or both a complementary treatment and a further active agent.
 58. A method of treatment of a subject, comprising administering to the subject a composition comprising a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof, wherein the subject has depression, anxiety, a pain condition, and/or an inflammatory condition, and wherein the compound is selected from:


59. The method according to claim 58, wherein the subject has treatment-resistant depression.
 60. The method according to claim 58, wherein the composition is administered by inhalation.
 61. The method according to claim 58, wherein the composition comprises a dosage amount of the compound or pharmaceutically acceptable salt thereof in the range of 0.05 mg to 100 mg.
 62. The method according to claim 58, wherein the composition comprises a dosage amount of the compound or pharmaceutically acceptable salt thereof in the range of 0.1 mg to 50 mg.
 63. The method according to claim 58, wherein the composition is administered with a complementary treatment, and the complementary treatment is psychotherapy.
 64. The method according to claim 58, wherein the composition is formulated in a dosage form selected from a tablet, a capsule, granules, powder, an aerosol, an injectable liquid, or a suppository. 